Chromosome abnormalities are often associated with genetic disorders, degenerative diseases, and cancer. The deletion or multiplication of copies of whole chromosomes and the deletion or amplifications of chromosomal segments or specific regions are common occurrences in cancer. In fact, amplifications and deletions of DNA sequences can be the cause of a cancer. For example, proto-oncogenes and tumor-suppressor genes, respectively, are frequently characteristic of tumorigenesis. The identification and cloning of specific genomic regions associated with cancer is therefore of interest both to the study of tumorigenesis and in developing better means of diagnosis and prognosis.
Cancer, like many diseases, is not the result of a single, well-defined cause, but rather can be viewed as several diseases, each caused by different aberrations in informational pathways, which ultimately result in apparently similar pathologic phenotypes. Identification of polynucleotides that correspond to copy number alterations in cancerous, pre-cancerous, or low metastatic potential cells relative to normal cells of the same tissue type, provides the basis for diagnostic tools, facilitates drug discovery by providing for targets for candidate agents, and further serves to identify therapeutic targets for cancer therapies that are more tailored for the type of cancer to be treated.
Identification of differentially altered genomic sequences also furthers the understanding of the progression and nature of complex diseases such as cancer, and is key to identifying the genetic factors that are responsible for the phenotypes associated with development of, for example, the metastatic phenotype. Identification of copy number alterations in various types of cancers can both provide for early diagnostic tests, and further serve as therapeutic targets.
Early disease diagnosis is of central importance to halting disease progression, and reducing morbidity. Analysis of a patient's tumor provides the basis for more specific, rational cancer therapy that may result in diminished adverse side effects relative to conventional therapies. Furthermore, confirmation that a tumor poses less risk to the patient (e.g., that the tumor is benign) can avoid unnecessary therapies.
Adenocarcinoma of the prostate is the most common malignancy in men over 50 yr in the USA; and the incidence increases with each decade of life. Prostate cancer generally is slowly progressive and may cause no initial symptoms, although there is considerable variation in phenotype. In late disease, symptoms of bladder outlet obstruction, ureteral obstruction, and hematuria may appear. Metastases to the pelvis, ribs, and vertebral bodies may cause bone pain. Locally advanced prostate cancer may exhibit extension of induration to the seminal vesicles and fixation of the gland laterally.
There are several known risk factors for getting prostate cancer, including age, ethnicity, genetics and diet. Age is generally considered the most important risk factor for prostate cancer. The incidence of prostate cancer rises quickly after the age of 60, and the majority of men will have some form of prostate cancer after the age of 80. The most common dietary culprit implicated in raising prostate cancer risk is a high fat diet, particularly a diet high in animal fats. Also, a few studies have suggested that a diet low in vegetables causes an increased risk of prostate cancer. A variety of different genetic factors are currently being researched. Men who carry mutations in BRCA1 or BRCA2 genes may have a 2 to 5 fold increase in prostate cancer risk. Men with high levels of testosterone or IGF-1 (insulin-like growth factor 1) also seem to be at a higher risk for developing prostate cancer.
Conventional screening for prostate cancer utilizes the prostate specific antigen (PSA) blood test, and the digital rectal exam (DRE). PSA is an enzyme produced in the prostate that is found in the seminal fluid and the bloodstream. An elevated PSA level in the bloodstream does not necessarily indicate prostate cancer, since PSA can also be raised by infection or other prostate conditions such as benign prostatic hyperplasia (BPH). Many men with an elevated PSA do not have prostate cancer. Nonetheless, a PSA level greater than 4.0 nanograms per milliliter of serum was established initially as the cutoff where the sensitivity for detecting prostate cancer was the highest and the specificity for detecting non-cancerous conditions was the lowest. A PSA level above 4.0 ng per milliliter of serum may trigger a prostate biopsy to search for cancer. The digital rectal exam is usually performed along with the PSA test, to check for physical abnormalities that can result from tumor growth.
The PSA test is an imperfect screening tool. A man can have prostate cancer and still have a PSA level in the “normal” range. Approximately 25% of men who are diagnosed with prostate cancer have a PSA level below 4.0. In addition, only 25% of men with a PSA level of 4-10 are found to have prostate cancer. With a PSA level exceeding 10, this rate jumps to approximately 65%.
With prostate cancer, once a cancer is diagnosed, a key clinical question is whether it will progress to clinically-evident disease and therefore merit treatment. For predicting clinical behavior, i.e. prognostication, the currently used indicators are tumor stage (a measure of tumor spread), tumor grade (a measure of tumor differentiation), and PSA (an indicator of tumor size). These current methods of prognostication are inadequate, because most prostate tumors present with low PSA, intermediate grade and early stage. Markers that would allow the stratification of tumors into genetic subtypes with distinct clinical behaviors are of great interest. Stable markers, such as DNA, are of particular interest. The present invention addresses these needs.